1. Field of the Invention
This invention concerns 9.alpha.,11.beta.- and 11.beta.-substituted estranes and their manufacture and their uses as active estrogenic and postcoital contraceptive agents.
2. General Background and Prior Art
It has long been recognized that estrogenic hormones are important pharmacologial materials which find a wide range of beneficial applications in human and veterinary therapy. Such applications include, for example, supplementing the estrogen levels in persons in need of the same; incorporation into birth control devices and compositions; and the like. Of the available natural and synthetic estrogens, estradiol has been among the most studied and is among the most active. Estradiol preparations are marketed commercially such as the product sold under the tradename Estrace. Estradiol is not orally active and must be administered parenterally.
It has also been long recognized that estrogens which are orally active are very attractive because of the obvious advantages of nontraumatic oral administration. In the late 1930's, Inhoffen et al described ethynyl estradiol (19-Nor-17A-pregna-1,3,5(10)triene-20-yne-3,17-diol. ##STR1## Naturwiss, 26, 96 (1938). This material is noted in such other early references as Inhoffen, et al. Ber. 71, 1024 (1938); German Pat. No. 702,063; British Pat. No. 516,444; and U.S. Pat. Nos. 2,243,887; 2,251,939; 2,265,976; and 2,267,257. As early as 1951, (Petit et al. Bull. Soc. Chim. France, 1951, 121) it was recognized that the material produced estrogenic effects in mammals when administered orally. This had led to its wide adoption as an oral estrogen and its marketing in a range of products and dosage forms under such proprietary names as, for example, Diogyn-E, Dyloform, Etinestryl, Ethidol, Estinyl, Etivex, Feminone, Inestra, Kolpolyn, Linoral, Lynoral, Novestrol, Oradiol, Orestralyn, Primogyn, and Progynon.
Ethynyl estradiol is also widely employed together with progestins such as norethindrone and noresthindrone acetate in oral contraceptives to give products substantially superior in effectiveness to materials without ethynyl estradiol. Examples of these ethynyl estradiol-containing contraceptive products include materials marketed under the proprietary names of Brevicon, Demulen, Loestrin, Modicon, Norinyl, Ortho-Novum, Ovcon, Oural, and Tri-Norinyl.
While the advantages of estradiol and ethynyl estradiol are substantial, as evidenced by their wide commercial adoption, these products are not without their drawbacks. These problems are extremely serious when viewed in terms of the large number of women who take preparations such as those listed above on a long and regular basis. These problems include enhancing the risk of endometrial carcinoma; induction of malignant carcinoma especially in the cervix, breast, vagina and liver; promotion of gallbladder disease, thromboembolic and thrombotic diseases, myocardial infarction, hepatic adenoma, elevated blood pressure, and hypercalcemia; and a worsening of glucose tolerance. These problems tend to manifest themselves at the dosage levels needed to achieve the desired primary estrogenic and contraceptive effects. Many of these side effects are considered to be dose-related. If more potent oral estrogens were available, they could be used in lower doses and the side effects could, at least in part, be reduced or eliminated.
The present invention provides a family of such more active estrogens. The following publications and United States Patent are believed to be of interest to these new materials and their preparation: P. J. Sykes and F. J. Rutherford, Tet. Lett. 37, 3393, (1971); K. Tsuda, S. Nozoe and Y. Okada, Chem. Parm. Bull. 11, (8), 1022, (1963); B. Magerlein and J. Hogg, J. Am. Chem. Soc. 80 2220 (1958); J. Baran, J. Med. Chem. 10, 1188, (1967); and U.S. Pat. No. 3,755,574, issued Aug. 28, 1973. In comparison to the disclosures of these references, the present invention provides materials not shown by them and provides easier access to the general class of 11.beta. and 9.alpha.,11.beta.-substituted estranes not previously available.
It is important to recognize that, notwithstanding the large volume of effort that has been devoted to research into the preparation and production and the testing of synthetic and naturally occurring steroids such as the estrogens, this is still very much an empirical field. Simple or seemingly insignificant shifts in one or two atoms or groups in a steroid can render a new compound active or inactive or change dramatically the entire character of its activity.